BACKGROUND: Although genetic variants in MYH7 are the most frequent cause of pediatric genetic dilated cardiomyopathy (DCM), there are no studies available describing this entity. We sought to describe clinical features, analyze variant location, and explore predictors of bad prognosis in pediatric MYH7-related DCM. METHODS AND RESULTS: We evaluated clinical records from 44 patients (24 men; median age at diagnosis, 0.54 [interquartile range, 0.01-10.8] years) with pathogenic/likely pathogenic variants in MYH7 diagnosed with DCM at pediatric age (<18 years) followed at 13 international centers. We also explored risk factors associated with a composite end point of end-stage heart failure defined as heart transplantation or heart failure-related death. Twenty-two patients (50%) were diagnosed at age <6 months, including 7 (16%) at birth. Left ventricular (LV) hypertrabeculation features were present in 15 (38%), particularly among patients with genetic variants in the head domain. After a median follow-up of 6.1 years (interquartile range, 1.9-13.4), 15 patients (36%) required a heart transplant (n=14) or died due to end-stage heart failure (n=1), 15 patients (36%) persisted with systolic dysfunction despite treatment, 12 (29%) had a significant increase in LV ejection fraction, and 2 were lost to follow-up. Overall, end-stage heart failure event rate was 25% at 5 years. New York Heart Association class III to IV (hazard ratio [HR], 7.67 [95% CI, 2.16-27.2]; P=0.002) and LV ejection fraction ≤35% (HR, 4.00 [95% CI, 1.11-14.4]; P=0.03) were the best predictors of bad prognosis. CONCLUSIONS: Pediatric MYH7-related DCM is characterized by early onset, frequent LV hypertrabeculation, and poor prognosis. Advanced New York Heart Association class and low LV ejection fraction emerged as predictors of end-stage heart failure.

• MeSH
• dilatační kardiomyopatie * genetika   patofyziologie   diagnóza   MeSH
• dítě MeSH
• fenotyp MeSH
• funkce levé komory srdeční MeSH
• genetická predispozice k nemoci MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mutace MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• srdeční myosiny * genetika   MeSH
• srdeční selhání genetika   patofyziologie   diagnóza   MeSH
• těžké řetězce myosinu * genetika   MeSH
• transplantace srdce * MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

IMPORTANCE: Impaired exercise capacity is a cardinal manifestation of obstructive hypertrophic cardiomyopathy (HCM). The Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) is a pivotal study characterizing the treatment effect of aficamten, a next-in-class cardiac myosin inhibitor, on a comprehensive set of exercise performance and clinical measures. OBJECTIVE: To evaluate the effect of aficamten on exercise performance using cardiopulmonary exercise testing with a novel integrated measure of maximal and submaximal exercise performance and evaluate other exercise measures and clinical correlates. DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified analysis from SEQUOIA-HCM, a double-blind, placebo-controlled, randomized clinical trial. Patients were recruited from 101 sites in 14 countries (North America, Europe, Israel, and China). Individuals with symptomatic obstructive HCM with objective exertional intolerance (peak oxygen uptake [pVO2] ≤90% predicted) were included in the analysis. Data were analyzed from January to March 2024. INTERVENTIONS: Randomized 1:1 to aficamten (5-20 mg daily) or matching placebo for 24 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was change from baseline to week 24 in integrated exercise performance, defined as the 2-component z score of pVO2 and ventilatory efficiency throughout exercise (minute ventilation [VE]/carbon dioxide output [VCO2] slope). Response rates for achieving clinically meaningful thresholds for change in pVO2 and correlations with clinical measures of treatment effect (health status, echocardiographic/cardiac biomarkers) were also assessed. RESULTS: Among 282 randomized patients (mean [SD] age, 59.1 [12.9] years; 115 female [40.8%], 167 male [59.2%]), 263 (93.3%) had core laboratory-validated exercise testing at baseline and week 24. Integrated composite exercise performance improved in the aficamten group (mean [SD] z score, 0.17 [0.51]) from baseline to week 24, whereas the placebo group deteriorated (mean [SD] z score, -0.19 [0.45]), yielding a placebo-corrected improvement of 0.35 (95% CI, 0.25-0.46; P <.001). Further, aficamten treatment demonstrated significant improvements in total workload, circulatory power, exercise duration, heart rate reserve, peak heart rate, ventilatory efficiency, ventilatory power, and anaerobic threshold (all P <.001). In the aficamten group, large improvements (≥3.0 mL/kg per minute) in pVO2 were more common than large reductions (32% and 2%, respectively) compared with placebo (16% and 11%, respectively). Improvements in both components of the primary outcome, pVO2 and VE/VCO2 slope throughout exercise, were significantly correlated with improvements in symptom burden and hemodynamics (all P <.05). CONCLUSIONS AND RELEVANCE: This prespecified analysis of the SEQUOIA-HCM randomized clinical trial found that aficamten treatment improved a broad range of exercise performance measures. These findings offer valuable insight into the therapeutic effects of aficamten. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05186818.

• MeSH
• dvojitá slepá metoda MeSH
• hypertrofická kardiomyopatie * patofyziologie   farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• spotřeba kyslíku fyziologie   MeSH
• srdeční myosiny MeSH
• tolerance zátěže * fyziologie   MeSH
• zátěžový test * metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

Mavakamten je selektivní reverzibilní inhibitor myosinu, který ovlivňuje kontrakci srdečního svalu. V současné době je jednoznačně prokázáno, že u pa cien tů s hypertrofickou kardiomyopatií a obstrukcí ve výtokovém traktu vede ke zmírnění obstrukce, zvýšení zátěžové kapacity a také k subjektivnímu zlepšení. Kromě toho se zdá, že by mohl být účinný také u pa cientů s hypertrofickou kardiomyopatií bez přítomné významné obstrukce. V tomto článku jsou přehledně shrnuty současné poznatky a klinická evidence u tohoto léku.

Mavacamten is a selective reversible myosin inhibitor that affects cardiac muscle contraction. Currently, there is clear evidence that in patients with hypertrophic cardiomyopathy with obstruction in the outflow tract, it leads to a reduction in obstruction, an enhancement of exercise capacity and also a subjective improvement. In addition, it appears that it could also be effective in patients with hypertrophic cardiomyopathy without significant obstruction. This article summarizes current knowledge and clinical evidence about this drug

• Klíčová slova
• mavakamten, studie PIONEER-HCM, studie EXPLORER-HCM, studie VALOR-HCM, studie MAVERICK-HCM,
• MeSH
• hypertrofická kardiomyopatie * chirurgie   farmakoterapie   genetika   klasifikace   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• srdeční myosiny antagonisté a inhibitory   terapeutické užití   MeSH
• tepový objem účinky léků   MeSH
• Check Tag
• lidé MeSH

• Klíčová slova
• mavakamten,
• MeSH
• benzylaminy aplikace a dávkování   MeSH
• echokardiografie metody   MeSH
• hypertrofická kardiomyopatie * diagnóza   epidemiologie   farmakoterapie   patologie   MeSH
• kardiovaskulární látky aplikace a dávkování   MeSH
• lidé MeSH
• srdeční myosiny antagonisté a inhibitory   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• novinové články MeSH

BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

• MeSH
• aplikace orální MeSH
• benzylaminy MeSH
• dvojitá slepá metoda MeSH
• hypertrofická kardiomyopatie * farmakoterapie   patofyziologie   MeSH
• kardiovaskulární látky * farmakologie   terapeutické užití   MeSH
• kontrakce myokardu účinky léků   fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• obstrukce výtoku ze srdeční komory farmakoterapie   patofyziologie   etiologie   MeSH
• senioři MeSH
• spotřeba kyslíku účinky léků   MeSH
• srdeční myosiny antagonisté a inhibitory   MeSH
• tolerance zátěže účinky léků   MeSH
• uracil analogy a deriváty   MeSH
• Valsalvův manévr MeSH
• zátěžový test * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

It is not well-understood how type 1 diabetes (T1DM) affects skeletal muscle histological phenotype, particularly capillarisation. This study aimed to analyze skeletal muscle myosin heavy chain (MyHC) fibre type changes and 3D capillary network characteristics in experimental T1DM mice. Female C57BL/6J-OlaHsd mice were categorized into streptozotocin (STZ)-induced diabetic (n = 12) and age-matched non-diabetic controls (n =12). The muscle fibre phenotype of the soleus, gluteus maximus, and gastrocnemius muscles were characterized based on the expression of MyHC isoforms, while capillaries of the gluteus maximus were assessed with immunofluorescence staining, confocal laser microscopy and 3D image analysis. STZ-induced diabetic mice exhibited elevated glucose levels, reduced body weight, and prolonged thermal latency, verifying the T1DM phenotype. In both T1DM and non-diabetic mice, the gluteus maximus and gastrocnemius muscles predominantly expressed fast-twitch type 2b fibers, with no significant differences noted. However, the soleus muscle in non-diabetic mice had a greater proportion of type 2a fibers and comparable type 1 fiber densities (26.2 ± 14.6% vs 21.9 ± 13.5%) relative to diabetic mice. T1DM mice showed reduced fiber diameters (P = 0.026), and the 3D capillary network analysis indicated a higher capillary length per muscle volume in the gluteus maximus of diabetic mice compared to controls (P < 0.05). Overall, T1DM induced significant changes in the skeletal muscle, including shifts in MyHC fibre types, decreased fibre diameters, and increased relative capillarisation, possibly due to muscle fibre atrophy. Our findings emphasize the superior detail provided by the 3D analytical method for characterizing skeletal muscle capillary architecture, highlighting caution in interpreting 2D data for capillary changes in T1DM.

• MeSH
• diabetes mellitus 1. typu metabolismus   patologie   MeSH
• experimentální diabetes mellitus * metabolismus   patologie   MeSH
• kapiláry * patologie   metabolismus   MeSH
• kosterní svaly * metabolismus   patologie   krevní zásobení   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• streptozocin MeSH
• těžké řetězce myosinu * metabolismus   MeSH
• zobrazování trojrozměrné MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cílem této práce je shrnout nové poznatky o patofyziologii a léčbě hypertrofické kardiomyopatie (HCM). Genetickou etiologii HCM můžeme vystopovat u cca 30–50 % nemocných. U genetických forem HCM jsou dominujícím mechanismem etiopatogeneze hyperkontraktilita sarkomery a porucha relaxace při depleci superrelaxované formy beta-izoformy těžkého řetězce myosinu. Tyto změny vedou ke zvýšené spotřebě energie a pravděpodobně přispívají také k progresi hypertrofie levé komory srdeční (LKS). Inhibice ATPázy srdečního myosinu koriguje hyperkontraktilitu a porušenou relaxaci u tkáňových a zvířecích modelů genetických forem HCM. Na klinické úrovni je HCM spojena s hyperkontraktilitou LKS, její diastolickou dysfunkcí a u části nemocných také s obstrukcí výtokového traktu LKS. Z terapeutického hlediska je důležitý management známek srdečního selhání u obstrukční i neobstrukční formy HCM, sledování výskytu fibrilace síní s adekvátní prevencí tromboembolických komplikací, prevence náhlé srdeční smrti u rizikových nemocných a specifická léčba fenokopií HCM. Novým registrovaným lékem u nemocných s obstrukční formou HCM je mavakamten, inhibitor ATPázy srdečního myosinu, který významně zlepšuje symptomatologii, toleranci zátěže, obstrukci ve výtokovém traktu a snižuje potřebu invazivní septální ablace. V recentních doporučeních byl zařazen do algoritmu léčby obstrukce výtokového traktu LKS jako lék druhé volby po selhání betablokátorů, verapamilu a diltiazemu.

We aimed to summarize the current knowledge regarding the pathophysiology and management of hypertrophic cardiomyopathy (HCM). Genetic aetiology of HCM can be traced in approximately 30-50% of probands. The predominant pathogenetic mechanisms of genetic HCM seem to be hypercontractility of sarcomere and its impaired relaxation due to depletion of super-relaxed isoform of cardiac myosin heavy chain. These processes may lead to an increased energetic consumption and possibly to progression of left ventricular (LV) hypertrophy. Inhibition of cardiac myosin ATPase corrects hypercontractility of sarcomere and its impaired relaxation both in tissue and animal models of genetic HCM. At the clinical level, HCM leads to LV hypercontractility, LV diastolic dysfunction and in a subset of patients also to a significant obstruction of LV outflow tract. The most important therapeutic goals are the management of heart failure in obstructive and non-obstructive form of HCM, surveillance of atrial fibrillation occurrence together with an adequate prevention of systemic thromboembolism, prevention of sudden cardiac death and specific treatment of HCM phenocopies. Mavacamten has been recently registered as a treatment of obstructive HCM. In this setting, the above-mentioned inhibitor of ATPase of cardiac myosin improves symptoms, exercise tolerance, obstruction of LV outflow tract and reduces the need for an invasive septal ablation. The latest guidelines have incorporated mavacamten into the therapeutic algorithm of management of LV outflow obstruction as the second choice after failure of betablockers, verapamil and diltiazem.

• Klíčová slova
• mavakamten,
• MeSH
• hypertrofická kardiomyopatie * etiologie   farmakoterapie   klasifikace   patofyziologie   MeSH
• kardiovaskulární látky aplikace a dávkování   metabolismus   škodlivé účinky   MeSH
• lidé MeSH
• srdeční myosiny antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Mavakamten je selektivní, alosterický a reverzibilní inhibitor srdečního myozinu. Tímto způsobem moduluje počet myozinových hlavic, které mohou vstupovat do stavu vzniku kontrakce, a tím snižuje pravděpodobnost tvorby systolických a reziduálních diastolických příčných můstků při kontrakci. Látka je aktuálně schválená a indikovaná k léčbě symptomatické hypertrofické obstrukční kardiomyopatie (oHCM) (New York Heart Association, NYHA, třída II–III) u dospělých pacientů. Aktuálně probíhá velká klinická studie, která se pokusí doplnit dlouhodobá data o bezpečnosti a účinnosti mavakamtenu ve zmíněné indikaci.

Mavakamten is a selective, allosteric and reversible inhibitor of cardiac myosin. In this way, it modulates the number of myosin heads that enter the state of onset of contraction, thereby reduce the likelihood of the formation of systolic and residual diastolic cross bridges during contraction. The molecule is currently approved and indicated for the treatment of symptomatic hypertrophic obstructive cardiomyopathy (oHCM) (New York Heart Association, NYHA, class II-III) in adult patients. A large clinical study is currently underway, which will attempt to supplement the long-term data on the safety and efficacy of mavacamten in the mentioned indication.

• Klíčová slova
• mavakamten, inhibitory srdečního myozinu,
• MeSH
• analýza dat MeSH
• hodnocení léčiv MeSH
• hypertrofická kardiomyopatie * diagnóza   farmakoterapie   MeSH
• klinická studie jako téma MeSH
• srdeční myosiny * antagonisté a inhibitory   farmakokinetika   farmakologie   terapeutické užití   MeSH
• Publikační typ
• přehledy MeSH

BACKGROUND & AIMS: Lymphedema cholestasis syndrome 1 or Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. The genetic background of this autosomal recessive disease was unknown up to now. METHODS: A total of 26 patients with Aagenaes syndrome and 17 parents were investigated with whole-genome sequencing and/or Sanger sequencing. PCR and western blot analyses were used to assess levels of mRNA and protein, respectively. CRISPR/Cas9 was used to generate the variant in HEK293T cells. Light microscopy, transmission electron microscopy and immunohistochemistry for biliary transport proteins were performed in liver biopsies. RESULTS: One specific variant (c.-98G>T) in the 5'-untranslated region of Unc-45 myosin chaperone A (UNC45A) was identified in all tested patients with Aagenaes syndrome. Nineteen were homozygous for the c.-98G>T variant and seven were compound heterozygous for the variant in the 5'-untranslated region and an exonic loss-of-function variant in UNC45A. Patients with Aagenaes syndrome exhibited lower expression of UNC45A mRNA and protein than controls, and this was reproduced in a CRISPR/Cas9-created cell model. Liver biopsies from the neonatal period demonstrated cholestasis, paucity of bile ducts and pronounced formation of multinucleated giant cells. Immunohistochemistry revealed mislocalization of the hepatobiliary transport proteins BSEP (bile salt export pump) and MRP2 (multidrug resistance-associated protein 2). CONCLUSIONS: c.-98G>T in the 5'-untranslated region of UNC45A is the causative genetic variant in Aagenaes syndrome. IMPACT AND IMPLICATIONS: The genetic background of Aagenaes syndrome, a disease presenting with cholestasis and lymphedema in childhood, was unknown until now. A variant in the 5'-untranslated region of the Unc-45 myosin chaperone A (UNC45A) was identified in all tested patients with Aagenaes syndrome, providing evidence of the genetic background of the disease. Identification of the genetic background provides a tool for diagnosis of patients with Aagenaes syndrome before lymphedema is evident.

• MeSH
• 5' nepřekládaná oblast genetika   MeSH
• cholestáza * genetika   MeSH
• HEK293 buňky MeSH
• intracelulární signální peptidy a proteiny * genetika   MeSH
• lidé MeSH
• lymfedém * diagnóza   genetika   metabolismus   MeSH
• myosiny genetika   metabolismus   MeSH
• novorozenec MeSH
• transportní proteiny genetika   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• akutní lymfatická leukemie farmakoterapie   genetika   patologie   MeSH
• akutní nemoc MeSH
• buněčný rodokmen genetika   MeSH
• genová přestavba MeSH
• histonlysin-N-methyltransferasa genetika   MeSH
• indukční chemoterapie metody   MeSH
• kineziny genetika   MeSH
• lidé MeSH
• lidské chromozomy, pár 11 genetika   MeSH
• lidské chromozomy, pár 6 genetika   MeSH
• malování chromozomů metody   MeSH
• mladiství MeSH
• myeloidní leukemie genetika   patologie   MeSH
• myosiny genetika   MeSH
• protoonkogenní protein MLL genetika   MeSH
• translokace genetická * MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• kazuistiky MeSH